Cocaine addiction is second only to opiates as the most problematic drug in the Americas with an enormous fee in human tragedy as well as in public health and safety. Currently there is no FDA approved pharmacological therapy for cocaine addiction, which has prompted the development of immuno-prophylactic alternatives. A therapeutic vaccine that elicits anti-cocaine antibodies will allow the rapid sequestration of the drug in circulation and reduce the amount and rate of its entry into the brain. A limiting factor t the success of small molecule drug vaccines is the low degree of immunity evoked by the addictive drug analog and lack of effective yet safe immune adjuvants. Also, clinical studies have unambiguously demonstrated that the design of proper haptens is critical for proper immune stimulation both in terms of amount of antibody elicited and antibody specificity. The goals of this proposal are to design and develop cocaine vaccines based on designed cocaine analogs in combination with a peptide nanofiber-based delivery platform for eliciting high titers of anti-cocaine antibodies and test their efficacy in a mouse motor activity assay. The work is divided into two aims: Aim 1) Design and synthesis of self-assembling peptide nanofiber-based cocaine vaccines. Aim 2) Test the efficacy of peptide nanofiber cocaine vaccine formulations in a mouse model. Our approach will be to design and chemically synthesize peptide nanofiber vaccines against cocaine. In aim 1, we will synthesize novel cocaine-based small molecule haptens modified at the P3 site with various chemical linkers and linker lengths. We will then conjugate the haptens to a self-assembling peptide domain using an orthogonal chemistry to produce peptide nanofibers that display the haptens in a multivalent fashion. In aim 2, we will investigate antibody responses against modified cocaine haptens coupled self-assembling peptides and the effect of linker chemistry and linker-length on the antibody titers. Mice will be immunized with synthetic cocaine nanofiber vaccines and the production of anti-cocaine antibodies will be investigated using a prime-boost regimen. Formulations that elicit high titers o anti-cocaine antibodies will be investigated for suppression of acute cocaine-induced motor activity and cocaine-induced behavioral sensitization. Success in these studies will provide us with insights into the development of small molecule drug analogs suitable for vaccination and the utility of self-assembling peptides as adjuvants for vaccines to treat addiction. Also, more broadly, completion of the proposed work will integrate the fields of synthetic chemistry, nanotechnology, immunology, and addiction to significantly impact human health.